DNA repair and repair diseases: between molecular models and clinical reality

To study the biological mechanisms of the repair of the radiation-induced DNA damage leads to two major medical applications: (1) the identification of the radiosensitive patients by using appropriate predictive assays in order to avoid toxicity due to radiation therapy and sometimes to chemotherapy; (2) the decrease of the radioresistance of tumour cells to obtain a better local control. To transpose fundamental biological knowledge from experimental in vitro clinic is delicate and sometimes too hasty, though necessary. In mechanistic terms, clinical features are once again a very rich and under-exploited approach to identify the molecular mechanisms of the DNA repair function. An exhaustive survey of the clinical cases of radiosensitivity with biological samples and with long course surveillance is an inverse approach, probably promising but still difficult to apply. Unlike classical reviews, this article attempts to identify the major genetic syndromes associated with radiosensitivity and cancer predisposition in order to deduce the different stages of major mechanisms of DNA double-strand breaks repair. Emphasis is placed on the importance of studying this repair at the functional level. Surprisingly, among the genetic syndromes associated to radiosensitivity there are some anomalies, not linked to DNA repair itself but to the intracellular trafficking. The repair function but therefore also the signalling are then logically therapeutic targets applicable in radiotherapy but with a very accurate ballistic sparing of the healthy tissues.